Extracellular Ca2+ concentration plays a very important role in various living body functions including maintenance of life. Thus, serum Ca2+ concentration is strictly controlled in a very narrow range by a number of regulatory mechanisms.
A parathyroid hormone (PTH) is a polypeptide hormone produced in and secreted from parathyroid glands, and mainly regulates serum Ca2+ concentration. This PTH increases serum Ca2+ concentration by accelerating bone resorption, and accelerating reabsorption of calcium in the kidney. Increase in the serum Ca2+ concentration inhibits the secretion of PTH, but on the contrary, decrease in the Ca2+ concentration accelerates the secretion of PTH, so it is believed that the serum Ca2+ concentration is controlled, in a sense, by a negative feedback mechanism.
Included in the hyperparathyroidism in which excessive secretion of PTH continuously occurs are primary hyperparathyroidism considered to be due to adenoma, hyperplasia, cancer or the like of the parathyroid itself and secondary hyperparathyroidism caused by renal function reduction and the like.
It has been reported that many renal insufficiency patients also suffer from secondary hyperparathyroidism. The secondary hyperparathyroidism is one of the causative diseases of renal osteodystrophy including ectopic calcification, and is considered to be the cause of lowering QOL of renal insufficiency patients due to bone fracture, bone pain and the like, and of the death of renal insufficiency patients caused by a cardiovascular disease considered to be resulted from calcification in the cardiovascular system. Thus, the secondary hyperparathyroidism is a big problem in the clinical field.
In the secondary hyperparathyroidism caused by renal insufficiency, excessive secretion of PTH is generated triggered by the reduction of serum Ca2+ concentration caused by lowering of the phosphorus excretion ability in the kidney and the reduction of active vitamin D. It is considered that this excessive secretion of PTH is continued and exacerbated by further reduction of renal function, parathyroid hyperplasia, resistance of the PTH target organ, and the like.
At present, a vitamin D replenishment therapy is mainly carried out as an internal therapy for the secondary hyperparathyroidism. However, since the vitamin D preparations increase the serum Ca2+ concentration, they have an administration limit, so that it is not the state of being able to carry out sufficient treatment. Based on the above, concern has been directed toward the development of a therapeutic agent for secondary hyperparathyroidism, which has high efficacy and does not increase serum Ca2+ concentration.
Calcium sensing receptor (CaSR) has been cloned initially as a G-protein coupled receptor (GPCR) which can sense extracellular Ca2+ in bovine parathyroid (Non-Patent Document 1). The CaSR has a function to change the intracellular Ca2+ concentration by sensing extracellular Ca2+ concentration, and thereby to regulate the production of molecules related to the Ca2+ metabolism regulation, typified by PTH. As a fact to support this, many reports have been published that active mutations of human CaSR cause familial hypercalcemia and inactive mutations of human CaSR cause familial hypocalcemia. In addition, reduction of sensitivity of the parathyroid gland for Ca2+ has been observed in both primary and secondary hyperparathyroidism.
It is considered that an agonistic regulatory agent of CaSR reduces PTH secretion without increasing serum Ca2+ concentration, by increasing the Ca2+ sensitivity through its direct action upon CaSR of the parathyroid gland. Recently, it has been reported that an agonistic regulatory agent of CaSR, cinacalcet, has an activity to inhibit PTH secretion by increasing the Ca2+ sensitivity of CaSR through its direct action upon CaSR of the parathyroid gland (Non-Patent Documents 2 and 3). Cinacalcet is expected to be a novel therapeutic agent for hyperparathyroidism which may be used concomitantly with a vitamin D preparation used already as the known remedy, a Ca2+-containing phosphate absorbent that has been used for the purpose of treating hyperphosphatemia, and the like.
However, it has been reported that cinacalcet has a strong activity to inhibit CYP2D6 which is one of the subtypes of cytochrome p450 (CYP). This CYP2D6 also plays an important role in the metabolism of various drugs used in the clinical field. Since cinacalcet inhibits CYP2D6, there is a danger of causing drug-drug interaction (DDI) by changing the pharmacokinetics of a drug through the delay of metabolism of a drug metabolized by CYP2D6 (Non-Patent Document 4). Based on the above, concern has been directed toward development of a strong CaSR regulatory agent free from CYP2D6 inhibitory activity.
It is considered that mRNA of CaSR is expressed in various tissues including the kidney and the parathyroid gland which is a main PTH secreting tissue and CaSR takes part in various physiological roles.
It is expected that an agent which regulates CaSR antagonistically or agonistically (CaSR regulator) could become a therapeutic agent of various diseases including bone disease and diseases of upper and lower digestive organs (Non-Patent Documents 5 and 6), diabetes mellitus (Non-Patent Documents 7 and 8), hypo-/hyper-function of pituitary (Non-Patent Document 9), and the like, in addition to the aforementioned hyperparathyroidism.
Regarding the CaSR regulator, there are reports of the following Patent Documents 1 to 3.
In the Patent Document 1, the compounds represented by the following formula (A) and formula (B) including a broad range of the compounds are disclosed. However, there is no specific disclosure on the compound of the present invention.

(wherein Ar, R, and R3 represent the following meanings.
Ar: a hydrophobic substance.
R: hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, indanyl, or 2-, 3- or 4-piperidyl.
R3: a monocyclic or bicyclic aryl or cycloalkyl having 5 or 6 ring constituting atoms, which may be substituted.
See the documents as described above for other signs.)
A compound represented by the following formula (C) is disclosed in the Patent Document 2. However, in the compound represented by formula (C), an amino group is directly linked to a nitrogen-containing ring. Further, there is no portion corresponding to R2 of the compound of the present invention.

(See the Documents as Described Above for Other Signs in the Formula.)
In addition, Patent Document 3 which has been filed by the present applicant and published after the priority date of the present application discloses a pyrrolidine derivative represented by the following formula (D). However, the nitrogen-containing hetero ring containing A and B is restricted to a pyrrolidine ring.

(wherein A and B represent —C(R7)(R7a)— or —C(O)—. See the documents as described above for other signs.)
Furthermore, regarding the piperidine derivative, there are the reports of the following Patent Documents 4 and 5.
Patent Document 4 describes that a piperidine derivative represented by the following formula (E) has an activity for preventing the calcium overload in the brain cells, and is effective for neurodegenerative diseases such as oxygen deficiency.
However, the compound (E) has no portion corresponding to R4 of the compound of the present invention. Further, it has no description on the effectiveness on a CaSR regulatory action and hyperparathyroidism.

(wherein Y means O, S, or NR, n means 0 to 4, and R3 means 3,4-methylenedioxyphenyl, phenyl, naphthyl, or a 5- or 6-membered hetero ring group. See the documents as described above for other signs.)
Patent Document 5 describes that a piperidine derivative represented by the following formula (F) has a tachykin receptor-agonistic activity, and is effective for pains, inflammation, allergy, and the like. However, for the compound (F), the substituent on a 4-position of the piperidine is an amide or an ester. Further, it has no description on the effectiveness of a CaSR regulatory action and hyperparathyroidism.

(wherein Z means O or N(R3). See the documents as described above for other signs.)    [Non-Patent Document 1] Brown et al., Nature, (England), 1993, vol. 366, p. 575-580    [Non-Patent Document 2] Cohen et al., Current Opinion in Pharmacology, (Holland), 2002, vol. 2, p/734-739    [Non-Patent Document 3] Joy et al., The Annals of Pharmacotherapy, (USA), 2004, vol. 38, p. 1871-1880    [Non-Patent Document 4] “Sensipar™ (registered trademark) (cinacalcet HCl) Tablets)”, [online], 2004, FDA [retrieved date: Mar. 28, 2005], Internet, (URL: http://www.fda.gov./cder/foi/label/2004/21688-Sensipar-lbl.pdf).    [Non-Patent Document 5] Jeannine et al., “The Journal of Clinical Investigation”, (USA), 1997, vol. 99, p. 2328-2333    [Non-Patent Document 6] Cheng et al., “The American Journal of Physiology-Gastrointestinal and Liver Physiology”, (USA), 2002, vol. 283, p. G240-G250    [Non-Patent Document 7] Bruce et al., “The Journal of Biological Chemistry”, (USA), 1999, vol. 274, p. 20561-20568    [Non-Patent Document 8] Straub et al., “The Journal of Biological Chemistry”, (USA), 2000, vol. 275, p. 18777-18784    [Non-Patent Document 9] Emanuel et al., Molecular Endocrinology, (USA), 1996, vol. 10, p. 555-565    [Patent Document 1] Pamphlet of International Publication No. 94/18959    [Patent Document 2] Pamphlet of International Publication No. 2005/115975    [Patent Document 3] Pamphlet of International Publication No. 2006/123725    [Patent Document 4] Pamphlet of International Publication No. 03/101964    [Patent Document 5] Pamphlet of International Publication No. 2006/004195